Preparation of quinolines

ABSTRACT

Quinoline and substituted quinolines are prepared by reacting aniline or a substituted aniline with an α, β-monounsaturated aldehyde in a high-boiling mineral oil by a method in which the high-boiling mineral oil is replaced when it becomes enriched with by-products, and the said mineral oil enriched with by-products is removed.

The present invention relates to a process for the preparation ofquinolines by reacting an aromatic amine with unsubstituted orsubstituted acrolein at elevated temperatures, in a mineral oil.

Quinolines are prepared by the Skraup method, from unsubstituted orsubstituted aniline and glycerol (Organikum, page 561, R. H. E. Manskeand M. Kulka, Org. Reactions 7, (1953), 59-98).

The method has a number of disadvantages and does not meet present-dayenergy and environmental requirements.

1. 3 moles of glycerol are required per mole of aniline.

2. One part of aniline requires from 2 to 3 parts of concentratedsulfuric acid, which is neutralized with alkali solution after thereaction. The salt solution to be disposed of still contains a verylarge amount of organic carbon.

3. The quinolines are obtained by an energy-consumptive steamdistillation procedure, which is followed by solvent extraction. Theaqueous raffinate contains solvents and residual product, which have tobe disposed of.

4. The oxidation of the dihydroquinoline intermediate is carried outwith nitrobenzene, arsenic pentoxide or iron(III) chloride.

The Doebner-Miller synthesis uses acrolein instead of glycerol, but hasthe other disadvantages of the Skraup synthesis.

It is an object of the present invention to provide a process for thepreparation of quinolines which does not have the stated disadvantagesand permits the by-products to be separated off in a simple manner.

We have found that this object is achieved, in accordance with theinvention, if unsubstituted or substituted aniline is reacted withacrolein or another α,β-unsaturated aldehyde at elevated temperatures,in a high-boiling mineral oil. In this procedure, only catalytic amountsof acid are required.

High-boiling mineral oils are high-boiling hydrocarbon fractions. ie. asa rule, refinery products having a boiling point of 150° C., such as gasoil, vacuum gas oil, heavy fuel oil, technical white oil, moltenparaffin wax or an aromatic hydrocarbon oil. It is advantageous to usevacuum gas oil having a boiling point of above 200° C., in particularfrom 350° to 500° C.

The reaction of p-toluidine with methacrolein to give3,6-dimethylquinoline can be represented by the following equation:##STR1##

It is surprising that this multi-stage reaction takes place with goodyields in a mineral oil at a temperature which is not excessively high,in the presence of only catalytic amounts of acid. The principal productis the desired quinoline or quinoline derivative. The tetrahydroderivative is obtained in amounts of only from 10 to 20%, based on theaniline employed, and can subsequently be converted to the desiredproduct in a simple manner, by dehydrogenation by conventional methods.

In general, quinolines of the formula ##STR2## where the individualradicals R¹, R² and R³ can be identical or different and are eachhydrogen or an aliphatic radical, and the radicals R¹ may furthermoreeach be halogen, alkoxy, amino, monoalkylamino or dialkylamino, or,together with two adjacent carbon atoms, may form an isoxazole, oxazole,thiazole, isothiazole, furan, thiophene, pyrrole, imidazole or pyrazoleradical, are prepared by reacting an aromatic amine of the formula##STR3## where R¹ has the above meanings, with an acrolein or one of itsacetals of the formula ##STR4## where R² and R³ have the above meanings,and the individual radicals R⁴ can be identical or different and areeach alkoxy or together are an oxygen atom. The starting materials IIand III can be reacted in stoichiometric amounts, or either componentcan be used in excess; advantageously, from 0.8 to 4, in particular from1 to 2, moles of starting material III are employed per mole of startingmaterial II. If starting materials II which carry 2 or 3 amino groups inthe molecule are used, as a rule not more than 1.5, expendiently from0.8 to 1.5, advantageously from 1 to 1.5, in particular from 1.1 to 1.3,moles of starting material III are employed per mole of startingmaterial II. If more than 1.5 moles of starting material III areemployed per mole of starting material II, phenanthrolines or thecorresponding triaza compounds containing 4 rings in the molecule areformed in increasing amounts when larger amounts of starting materialIII are used. Preferred starting materials II and III, and accordinglypreferred end products ducts I, are those of the formulae where theindividual radicals R¹, R² and R³ can be identical or different and areeach hydrogen, carboxyl or alkyl of 1 to 8, in particular 1 to 4, carbonatoms, and the radicals R¹ may furthermore each be fluorine, chlorine,bromine, amino, alkoxy, acylamino, or monoalkyl- or dialkylamino whereeach alkyl is of 1 to 8, in particular 1 to 4, carbon atoms, or theradicals R¹ together with two adjacent carbon atoms form an isoxazole,oxazole, thiazole, isothiazole, furan, thiophene, pyrrole, imidazole orpyrazole radical, and the individual radicals R⁴ can be identical ordifferent and are each alkoxy of 1 to 4 carbon atoms, or together are anoxygen atom. The above radicals can be further substituted by groups oratoms which are inert under the reaction conditions, eg. chlorine,bromine, alkyl or alkoxy, each of 1 to 4 carbon atoms, nitro oracylamino.

Examples of suitable starting materials II are aniline and o-methyl-,o-ethyl-, o-propyl-, o-isopropyl-, o-butyl-, o-isobutyl-, o-sec.-butyl-,o-tert.-butyl-, o-methoxy-, o-ethoxy-, o-propoxy-, o-isopropoxy-,o-butoxy-, o-isobutoxy-, o-sec.-butoxy-, o-tert.-butoxy-,o-dimethylamino-, o-diethylamino-, o-dipropylamino-, o-dibutylamino-,o-diisobutylamino-, o-di-sec.-butylamino-, o-di-tert.-butylamino-,o-N-methyl-N-ethylamino-, o-chloro-, o-bromo- and o-carboxyaniline;anilines which, instead of the above dialkylamino groups, aresubstituted by the corresponding monoalkylamino groups or byunsubstituted amino; anilines which are meta-substituted orpara-substituted by the above groups; anilines which are disubstitutedin the 2,4-, 2,3-, 2,5-, 3,4- or 3,5-position by identical or differentgroups from amongst those stated above; and thionaphthene, indole,benzoxazole, benzopyrazole, benzimidazole, benzisoxazole, benzothiazole,benzisothiazole or benzofuran which is substituted in the 4-, 5-, 6- or7-position by amino.

Examples of suitable starting materials III are acrolein which isunsubstituted or substituted in the 2-position and/or 3-position byidentical or different substituents from the group consisting of methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl and tert.-butyl;and the dimethyl-, diethyl-, dipropyl- and diisopropyl-, dibutyl-,diisobutyl-, di-sec.-butyl-, di-tert.- butyl acetals of the aboveacroleins. Preferred reactive α,β-unsaturated aldehydes are acrolein,methacrolein, crotonaldehyde, cinnamaldehyde and ethylacrolein.

The reaction according to the invention is preferably carried out usingan acidic catalyst.

The catalysts used can be either insoluble or soluble in the mineraloil, and are accordingly dissolved, emulsified or suspended in themineral oil. The reaction is carried out in general in the presence ofan inorganic or organic acid, as a rule a catalytic amount,advantageously from 0.001 to 0.4, in particular from 0.005 to 0.05,equivalent, of acid being employed per mole of starting material II.Instead of monobasic acids, it is also possible to use equivalentamounts of polybasic acids. Examples of suitable acids are sulfonicacids, such as benzenesulfonic, p-toluenesulfonic anddodecylbenzenesulfonic acid, aliphatic carboxylic acids, such as oxalicacid, formic acid, acetic acid, propionic acid, caproic acid, capricacid, 3,5,5-trimethylhexanoic acid, lauric acid, palmitic acid, stearicacid, 2-ethylhexanecarboxylic acid, 2-ethylbutyric acid,2-methylbutanoic acid, glycolic acid, lactic acid, pyruvic acid,tartaric acid, caprylic acid, trimethylacetic acid, succinic acid,isovaleric acid, valeric acid, glutaric acid and adipic acid,cycloaliphatic, araliphatic and aromatic carboxylic acids, such asbenzoic acid, 2,3-, 2,4-, 2,5- and 2,6-dimethylbenzoic acid, melliticacid, phenylpropionic acid, o-, m- and p-chlorobenzoic acid,cyclohexanecarboxylic acid, cyclopentanecarboxylic acid, phenylaceticacid, α- or β-naphthoic acid, phthalic acid, o-, m- and p-toluic acid,isophthalic acid and terephthalic acid, acidic ion exchangers andmixtures of these. Toluenesulfonic acids, benzenesulfonic acid,dodecylbenzenesulfonic acid, sulfuric acid, sulfuric acid half esters,such as alkylsulfuric acid, phosphoric acid and its partially esterifiedderivatives, and boric acid and its acidic derivatives are preferred. Itis also possible to use anhydrides, such as phosphorus pentoxide, sulfurdioxide or boron oxide. If the starting materials, in particularstarting material II, contain carboxyl groups, ie. are themselves acids,an additional acid need not be used, the starting material also beingemployed as the catalyst. In such cases, it is expedient to use from 0.8to 4, advantageously from 1 to 2, moles of starting material III permole of starting material II.

The catalysts which are soluble in the mineral oil are added to thelatter in general in amounts of from 0.01 to 25, preferably from 0.1 to20, in particular from 1 to 7, % by weight, based on the mineral oil.

The quinoline synthesis is carried out in general at from 50° to 350°C., preferably from 80° to 250° C., in particular from 100° to 200° C.

Examples of suitable reactors are stirred kettles, but the novel processis advantageously carried out using vertical cylindrical reactors, suchas bubble tray columns, bubble columns or packed columns. The startingmaterial or materials are as a rule introduced in gaseous or liquid format the base of the reactor filled with mineral oil. It may beadvantageous to dilute the vaporized starting material with an inertgas, examples of suitable inert gases being steam, carbon dioxide and,preferably, nitrogen.

The reaction products are taken off in gaseous form at the top of thereactor and, advantageously, are then condensed. The condensation canalso be followed by a purification stage, for example a distillation orfractionation.

The novel process can be carried out batchwise or continuously, thelatter method being preferred. In the continuous procedure, it may beadvantageous to introduce fresh mineral oil continuously and remove thespent solvent constantly, for example when the reaction is one in whichcrack products and polymers are formed; in this manner, the crackproducts are continuously removed from the reactor, together with themineral oil.

In an equally preferred embodiment, the reactants are fed simultaneouslyand gradually into the catalyst-containing mineral oil, without thereaction products being removed continuously. When the mixture hasbecome enriched with the end products, the feed of the startingmaterials is discontinued, and the useful products are separated fromthe mineral oil by distillation. High boiling by-products remain in theoil. The major part of the oil can be re-used, but some of it has to beremoved.

As a rule, it is not economical to work up and recycle the mineral oilremoved, since the mineral oil is in general available cheaply, forexample in the form of fuel oil or vacuum gas oil. Advantageously,therefore, the mineral oil removed, which contains crack products, isfed for combustion, and fresh mineral oil is introduced into thereactor.

The novel process has the following substantial advantages over theprior art processes:

Catalytic amounts of acids are adequate, and the neutralization of largeamounts of sulfuric acid is dispensed with. Polymers and condensateswhich are unavoidable in reactions of aldehydes with amines remain inthe mineral oil; the latter need not be regenerated and, if desiredafter the catalyst has been separated off, is advantageously fed forcombustion in a power station. Moreover, the process is substantiallymore economical both in its technical implementation and in its energyconsumption. Finally, combustion of the reaction medium and of thebyproducts present therein results in less environmental pollution.

EXAMPLE 1

In the apparatus shown in FIG. 1, 123 g/hour of acroline and 283 g/hourof 3-chloro-2-methylaniline were fed from the vessels 2a and 2b, bymeans of metering pumps 1a and 1b, into pre-evaporators 3a and 3b, andwere vaporized therein together with, in each case, 30 liters/hour of N₂at 170° C., and the vapor was then introduced into the reactor 5 via atwo-material nozzle 4. The reaction temperature was 150° C.

The reactor consisted of a double-walled tube which was 1.25 m long andhad a diameter of 65 mm. A perforated plate with 5 mm holes was located3 cm above the nozzle entrance. The upper part of the reactor was filledwith 3 liters of 5×5 mm glass rings.

The reactor contained 1.2 kg of vacuum gas oil of boiling point >350°C., with 5% by weight of dodecylbenzenesulfonic acid as a catalyst.

The resulting water of reaction and unreacted acrolein were condensed ina condenser 6, and collected in a collecting vessel 7. The7-chloro-8-methylquinoline formed was recovered from the vacuum gas oilin the reactor by fractional distillation.

Based on the starting materials fed in per hour, 192 g of distillate(bp. 119° C./2 mm Hg) were obtained which, according to gaschromatography, contained 98% by weight of 7-chloro-8-methylquinoline,ie. 53%, based on 3-chloro-2-methylaniline employed.

A further fraction contained 82.6 g of7-chloro-8-methyltetrahydroquinoline, and this could be converted to7-chloro-8-methylquinoline by heating with 2-chloro-5-nitrotoluene. Thisincreased the yield to 76%, based on 3-chloro-2-methylaniline employed.

EXAMPLE 2

The procedure described in Example 1 was followed, except that 1.2 kg ofvacuum gas oil of boiling point 350° C. were employed, together with 1%by weight of dodecylbenzenesulfonic acid as a catalyst. Based on thestarting materials fed in per hour, 210 g of distillate were obtained ata boiling point of 119° C./2 mm Hg; this distillate contained 98% byweight of 7-chloro-8-methylquinoline, corresponding to a yield of 58%,based on 3-chloro-2-methyl aniline employed.

A further fraction contained 36 g of7-chloro-8-methyltetrahydroquinoline, and this could be oxidized to7-chloro-8-methylquinoline by heating with 2-chloro-5-nitrotoluene. Thisincreased the yield at 68%, based on 3-chloro-2-methylaniline employed.

EXAMPLE 3

The procedure described in Example 1 was followed, except that 187g/hour of ethylacrolein and 283 g/hour of 3-chloro-2-methylaniline wereemployed. Distillation gave 335 g of distillate at a boiling point of125° C./2 mm Hg. This distillate contained 75% by weight of3-ethyl-7-chloro-8-methylquinoline and 22% by weight of3-ethyl-7-chloro-8-methyltetrahydroquinoline, corresponding to aquinoline yield of 60%, based on 3-chloro-2-methylaniline employed.

The tetrahydro compound could likewise be converted to3-ethyl-7-chloro-8-methylquinoline by oxidation with2-chloro-6-nitrotoluene. This increased the yield to 77.5%.

EXAMPLE 4

The procedure described in Example 1 was followed, except that 123g/hour of acrolein and 214 g/hour of 3-methylaniline were employed.Distillation gave 140 g of distillate of boiling point 128° C./15 mm hg.This distillate contained 92% by weight of 8-methylquinoline,corresponding to a yield of 45%, based on 3-methylaniline employed.

EXAMPLE 5

The procedure described in Example 1 was followed, except that 107g/hour of 4-toluidine and 84 g/hour of methacrolein were employed. Theproduct was distilled off under 5 mbar until the bottom temperaturereached 250° C., and 110 g (70% of theory) of 3,6-dimethylquinoline ofmelting point 50° C. were obtained by crystallization with xylene.

EXAMPLE 6

The procedure described in Example 1 was followed, except that 130g/hour of 2-chloroaniline and 84 g/hour of crotonaldehyde were employed.Distillation from the oil bed under 5 mbar until the bottom temperaturereached 250° C., and crystallization of the distillate with xylene, gave101 g (57% of theory) of 8-chloro-2-methylquinoline of melting point 64°C.

We claim:
 1. In a process for the preparation of quinoline or asubstituted quinoline by reacting aniline or a substituent aniline withan α,β-mono-unsaturated aldehyde or an acetal thereof in the presence ofan acid, the improvement which comprises: reacting the aniline with theunsaturated aldehyde or acetal thereof at a temperature of from 80° to250° C. in the presence of a mineral oil having a boiling point above150° C., said mineral oil being selected from the group consisting ofgas oil, vacuum gas oil, heavy fuel oil, technical white oil, moltenparaffin wax and an aromatic hydrocarbon oil, said reaction furthertaking place in the presence of from 0.1 to 20% by weight of an organicacid catalyst based on the weight of the mineral oil.
 2. The process ofclaim 1, wherein the acid catalyst is an organic acid that is soluble inthe mineral oil.
 3. The process of claim 1, wherein the quinoline orsubstituted quinoline and the corresponding tetrahydroquinoline formedin the reaction are continuously recovered in a first stage byfractional distillation and are passed to a second stage wherein thetetrahydroquinoline or substituted tetrahydroquinoline is oxidized toquinoline or substituted quinoline.
 4. The process of claim 3, whereinin the first stage a portion of the mineral oil enriched with byproductsis continuously withdrawn as a sidestream from the reaction mixture andfresh mineral oil is added to the reaction mixture.